Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyper-androgenic stimulation caused by an excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neri, et al., Endocrinol. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is 5.alpha.-dihydrotestosterone ("DHT"), formed locally in the target organ by the action of testosterone-5.alpha.-reductase (or simply 5.alpha.-reductase). Inhibitors 5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. Nos. 4,377,584, issued Mar. 22, 1983, and 4,760,071, issued Jul. 26, 1988, both assigned to Merck & Co., Inc. It is now known that a second 5.alpha.-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (November 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5.alpha.-reductase 1 (or 5.alpha.-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5.alpha.-reductase 2 (or 5.alpha.-reductase type 2).
U.S. Pat. No. 5,237,064 describes a process for producing 7.beta.-substituted 5.alpha.-androstan-3-ones. U.S. Pat. No. 5,470,976 describes the stereoselective hydrogenation of the delta-5 double bond of a 17-substituted azasterold. U.S. Pat. Nos. 5,120,847 and 5,021,575 relate to the insertion of a double bond at the 1,2 position of a 4-azasteroid.
The instant invention provides an improved process for the synthesis of 16.alpha.- or .beta.-substituted 4-aza-5.alpha.-androst-1-en-3-ones and 5.alpha.-androstan-3-ones. 16-stubstituted 4-aza-5.alpha.-androstan-3-ones are described in U.S. Pat. No. 5,719,158. The present invention provides a process of formation of a methylsulfonate and nucleophilic displacement thereof that proceeds without side-reaction with the ene-lactam functionality. Also provided by the present invention are intermediates useful in the present process.